Description: The focus of this renewal is on understanding the molecular consequences of neurotrophic factors and how these molecular interactions change in the aged brain. During the past funding period, we have demonstrated that BDNI and GNDF can regulate the transcription of the GIuR2 receptor via the neuron-restrictive silencer element (NRSE). Concomitantly, our colleagues in project 15 have shown an increase in GIuR2 synthesis in late-phase LTP. There is growing evidence that BDNF is involved in neuronal plasticity, including LTP. We plan to extend these findings to GDNF. Our hypothesis is that the role of BDNF and GDNF in LTP is via transcriptional regulation of GluR2 synthesis. We will use the approach of examining dynamic changes in trophic factor expression resulting from LTP and compare these responses in young and old animals. We will determine if alterations in neurotrophic-factor regulation of GluR2 synthesis are important in the observed age-related deficit in late-phase LTP. We will examine the effect of GDNF and GFRa1 heterozygous gene deletions on GIuR2 Flip/Flop splice variants. A second hypothesis is that neurotrophins are important in the cellular response to oxidative stress. We plan to examine if the heterozygous gene deletions for GDNF or GFRal alter the sensitivity of the brain to oxidative insults and to examine if antioxidant treatments can improve trophic factor expression in the aged brain.